Elmorsy Mohamed R, Yousef Sara H, Abdel-Latif Ehab, Badawy Safa A
Department of Chemistry, Faculty of Science, Mansoura University, Mansoura, 35516, Egypt.
BMC Chem. 2025 Jun 11;19(1):164. doi: 10.1186/s13065-025-01535-w.
Compound 2-(2-cyanoacetamido)pyrazine (3) serves as a key precursor for synthesizing various new pyrazine-linked heterocycles, including pyridine, thiazole, pyrazole, chromene, and pyrazolotriazine derivatives. Pyrazine-pyridone analogues 5a-d were obtained by reacting compound 3 with substituted 2-(arylidene)malononitriles (4a-d). Substituted pyrazine-thiazoles (8 and 9) were synthesized by condensation with phenyl isothiocyanate, followed by cyclization using ethyl bromoacetate or chloroacetone. Pyrazine-chromenes (14, 15) and pyrazine-naphthoxazines (16, 17) were prepared by reacting salicylaldehyde and naphthol derivatives. Additionally, pyrazine-pyrazolotriazines 19a and 19b were formed by coupling diazotized aminopyrazoles (18a and 18b). The structures of the synthesized compounds were confirmed using IR, HNMR, and C NMR spectroscopy. Antibacterial activity was evaluated against gram-positive (S. aureus and B. subtilis) and gram-negative (E. coli and K. pneumoniae) bacteria. Notably, compound 5c exhibited strong activity against E. coli (15 mm), and 5d showed potent inhibition against S. aureus (18 mm), comparable to the reference antibiotic gentamicin. Molecular docking studies revealed that pyrazine-pyridone derivative 5d displayed the highest binding affinity (S = -7.4519 kcal/mol, RMSD = 1.2498), attributed to two key interactions: one hydrogen-donor and one π-hydrogen bond with the bacterial target (PDB: 4DUH). These in silico findings suggest that 5d can effectively bind to a critical bacterial enzyme, reinforcing its potential as a promising antibacterial agent. Moreover, the Swiss ADME study provides an in-depth analysis of the drug-like properties and pharmacokinetic attributes of these compounds, further supporting their potential for drug development. Overall, compound 5d was the most promising candidate for further antibacterial drug design and optimization.
化合物2-(2-氰基乙酰氨基)吡嗪(3)是合成各种新型吡嗪连接杂环化合物的关键前体，这些杂环化合物包括吡啶、噻唑、吡唑、色烯和吡唑并三嗪衍生物。吡嗪-吡啶酮类似物5a-d是通过化合物3与取代的2-(亚芳基)丙二腈(4a-d)反应得到的。取代的吡嗪-噻唑(8和9)是通过与异硫氰酸苯酯缩合，然后用溴乙酸乙酯或氯丙酮环化合成的。吡嗪-色烯(14,15)和吡嗪-萘并恶嗪(16,17)是通过水杨醛和萘酚衍生物反应制备的。此外，吡嗪-吡唑并三嗪19a和19b是通过重氮化氨基吡唑(18a和18b)偶联形成的。合成化合物的结构通过红外光谱、核磁共振氢谱和碳谱进行了确证。对革兰氏阳性菌(金黄色葡萄球菌和枯草芽孢杆菌)和革兰氏阴性菌(大肠杆菌和肺炎克雷伯菌)进行了抗菌活性评估。值得注意的是，化合物5c对大肠杆菌表现出较强活性(抑菌圈直径15 mm)，5d对金黄色葡萄球菌表现出强效抑制作用(抑菌圈直径18 mm)，与参考抗生素庆大霉素相当。分子对接研究表明，吡嗪-吡啶酮衍生物5d表现出最高的结合亲和力(S = -7.4519 kcal/mol，RMSD = 1.2498)，这归因于两个关键相互作用：一个氢键供体和一个与细菌靶点(PDB: 4DUH)的π-氢键。这些计算机模拟结果表明，5d能有效地与一种关键细菌酶结合，增强了其作为一种有前景的抗菌剂的潜力。此外，瑞士ADME研究对这些化合物的类药性质和药代动力学属性进行了深入分析，进一步支持了它们在药物开发方面的潜力。总体而言，化合物5d是进一步进行抗菌药物设计和优化的最有前景的候选物。
